- Ophthalmic Plastic & Reconstructive Surgery
- Pediatric Oculoplastics
Medical Education: Case Western Reserve School of Medicine (2006) OH
Residency: Columbia University Medical Center Ophthalmology (2010) NY
Board Certification: American Board of Ophthalmology, Ophthalmology (2012)
Internship: Memorial Sloan-Kettering Cancer Center (2007) NY
Fellowship: MD Anderson Cancer Center (2012) TX
Board Certification, American Board of Ophthalmology (2012)
Malignant optic glioma masked by suspected optic neuritis and central retinal vein occlusion.
Radiology case reports
2019; 14 (2): 226–29
Malignant optic glioma presents a clinical and diagnostic challenge, as early imaging findings overlap with other more common causes of optic nerve enhancement and enlargement, potentially leading to delay in diagnosis. This rare diagnosis carries an extremely poor prognosis, with death usually occurring within 1 year. We present a case of malignant optic glioma that was initially diagnosed as optic neuritis and central retinal vein occlusion, and we emphasize the importance of serial imaging and definitive biopsy to promote early diagnosis and treatment of this entity.
View details for PubMedID 30450148
Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection.
Ophthalmic plastic and reconstructive surgery
Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms.
View details for PubMedID 26108057
Intraocular Pressure Changes in Emergent Surgical Decompression of Orbital Compartment Syndrome
JAMA OTOLARYNGOLOGY-HEAD & NECK SURGERY
2015; 141 (6): 562-565
Orbital compartment syndrome is an acute rise in intraorbital volume resulting in increased intraorbital pressure and possible ischemic compromise of the optic nerve. Tonometric pressure measurement of intraocular pressure can aid surgeons in the diagnosis of this condition and in choosing the need to proceed with emergent surgical intervention. In addition, we present an unexpected cause of orbital compartment syndrome following routine frontal sinus irrigation.An emergent lateral canthotomy and cantholysis followed by endoscopic medial wall decompression were performed, with intraocular pressure measurements performed throughout the evolution of this successful, and vision sparing, set of procedures. The techniques and continuous improvements in intraocular pressure measurements are described.There are only rare reports of the progression of intraocular pressure prior to, and concurrent with, surgical orbital decompression. While no absolute threshold for intraocular pressure exists for when surgical decompression should be performed, the decision of when and which decompression procedures to undertake should be based on clinical judgment and experience. Availability of tonometry in the operating room serves to measure response to management in these rare but challenging settings where intervention may be required to prevent irreversible visual loss.
View details for DOI 10.1001/jamaoto.2015.0524
View details for Web of Science ID 000356458300012
View details for PubMedID 25880995
Ophthalmic complications of targeted cancer therapy and recently recognized ophthalmic complications of traditional chemotherapy.
Survey of ophthalmology
2014; 59 (5): 493-502
As our understanding of cancer pathophysiology has increased, so have the number of targeted therapeutic agents available. By targeting specific molecules involved in tumorigenesis, targeted therapeutic agents offer the potential for significant efficacy against tumor cells while minimizing the adverse effects. We highlight the recently recognized ophthalmic complications of targeted cancer therapy, as well as recently recognized complications of traditional chemotherapeutic agents.
View details for DOI 10.1016/j.survophthal.2014.02.004
View details for PubMedID 25130892
- Ophthalmic complications of targeted cancer therapy and recently recognized ophthalmic complications of traditional chemotherapy SURVEY OF OPHTHALMOLOGY 2014; 59 (5): 493-502
Multidisciplinary Management of Primary Adenoid Cystic Carcinoma of the Eyelid With Perineural Invasion.
Ophthalmic plastic and reconstructive surgery
Primary cutaneous adenoid cystic carcinoma of the eyelid is an extremely rare entity with the propensity to recur locally, spread to regional lymph nodes, and invade perineural spaces. Of the 8 cases previously reported in the literature, only 2 were noted to be associated with perineural invasion, and neither of these was treated with radiation therapy. The authors report the case of a 35-year-old woman who presented with a progressively enlarging left lower eyelid lesion. An excisional biopsy with wide margins revealed a diagnosis of primary adenoid cystic carcinoma of the eyelid with perineural invasion. Because of the high risk of recurrence associated with perineural invasion, the patient received postoperative adjuvant radiation in the form of 50 Gy relative biological effectiveness of proton beam therapy to the postoperative tumor bed and to the infraorbital nerve tracking back to the apex of the orbit, followed by a 10-Gy boost to the lower eyelid tumor bed with orthovoltage x-rays.
View details for DOI 10.1097/IOP.0b013e3182831bbe
View details for PubMedID 23446295
- Epidermal Growth Factor Receptor Inhibitors for Treatment of Orbital Squamous Cell Carcinoma ARCHIVES OF OPHTHALMOLOGY 2012; 130 (12): 1608-1611
Outcomes of Dacryocystorhinostomy in Patients With Head and Neck Cancer Treated With High-Dose Radiation Therapy
42nd Annual Fall Scientific Symposium of the American-Society-of-Ophthalmic-Plastic-and-Reconstructive-Surgery (ASOPRS)
LIPPINCOTT WILLIAMS & WILKINS. 2012: 196–98
To evaluate the outcomes of dacryocystorhinostomy (DCR) in patients with head and neck cancer treated with high-dose radiation therapy.The clinical records of 43 consecutive patients with head and neck cancer who underwent DCR after high-dose external beam radiation therapy plus ablative surgery and/or chemotherapy between December 2001 and April 2011 were retrospectively reviewed.There were 23 men and 20 women. The median age was 56 years (range, 2-92 years). Thirty-one patients were Caucasian, 6 Hispanic, 4 Asian, and 2 African American. Thirty patients (70%) presented with epiphora, 3 (7%) with dacryocystitis, and 10 (23%) with both epiphora and dacryocystitis. Symptoms were unilateral in 34 patients (79%) and bilateral in 9 patients (21%). The most common primary cancer diagnoses were squamous cell carcinoma (n = 14), sarcoma (n = 8), adenoid cystic carcinoma (n = 4), and basal cell carcinoma (n = 4). The most common primary tumor locations were the sinonasal cavity (n = 16), maxillary sinus (n = 9), palate (n = 3), and ethmoid sinus (n = 3). Thirty-seven patients (43 eyes) had DCR with silicone tube placement, and 6 patients (7 eyes) had DCR with Pyrex glass tube placement. Following DCR, 31 patients (72%) had resolution of their symptoms, and 12 patients (28%), 9 with silicone tubes and 3 with Pyrex glass tubes, had persistent or recurrent epiphora (DCR failure). The most common reason for failure was significant residual canalicular and nasal mucosal scar tissue. Eight of these 12 patients underwent additional surgery, most commonly with placement of a Pyrex glass tube. Seven (35%) of the 20 patients who underwent DCR less than 12 months after radiation therapy and 5 (21%) of the 23 patients who underwent DCR at least 12 months after radiation therapy had recurrent symptoms.Dacryocystorhinostomy in patients with head and neck cancer previously treated with high-dose radiation therapy is generally successful, especially when delayed until at least 12 months after the completion of radiation therapy. A common reason for DCR failure after high-dose radiation therapy is severe canalicular and nasal mucosal scarring.
View details for DOI 10.1097/IOP.0b013e31824c11df
View details for Web of Science ID 000304530700021
View details for PubMedID 22460683
- Prognostic Accuracy of the Seventh Edition vs Sixth Edition of the American Joint Committee on Cancer Tumor Classification for Adenoid Cystic Carcinoma of the Lacrimal Gland ARCHIVES OF OPHTHALMOLOGY 2012; 130 (5): 664-666
Retinoblastoma presenting in a child with hypomelanosis of Ito.
The open ophthalmology journal
2011; 5: 55-58
To describe a case of a child with a known history of pigmentary mosaicism suggestive of Hypomelanosis of Ito presenting with unilateral leukocoria, who was ultimately diagnosed with retinoblastoma.A report of a 16-month-old girl with pigmentary mosaicism and unilateral retinoblastoma.A previously healthy 16-month-old girl with a diagnosis of a mosaic hypopigmentation at the age of 6 months based on a linear and whorled pattern of skin hypopigmentation along the lines of Blaschko, presented with unilateral strabismus, leukocoria, retinal detachment, and sub-retinal exudation. Hypomelanosis of Ito and other similar neurocutaneous syndromes are known to be associated with abnormal retinal pigmentation, vascular abnormalities, and retinal detachment. Examination included a fluorescein angiogram, ultrasonography, and an MRI of the brain and orbits that demonstrated features consistent with retinoblastoma. Given these findings and a flat electroretinogram, the eye was enucleated with final pathologic confirmation of retinoblastoma.Previously unreported presentation of unilateral retinoblastoma in a child with pigmentary mosaicism.
View details for DOI 10.2174/1874364101105010055
View details for PubMedID 22216075
- Acute Orbitocranial Inflammation Following Radioimmunotherapy for Non-Hodgkin Lymphoma OPHTHALMIC PLASTIC AND RECONSTRUCTIVE SURGERY 2010; 26 (3): 210-212
Intravitreal injection of tissue plasminogen activator as treatment for an occluded pars plana glaucoma tube.
Clinical ophthalmology (Auckland, N.Z.)
2009; 3: 91-93
Implanting glaucoma tubes through the pars plana in the setting of a corneal transplant is becoming more common, and there are unique problems associated with such a procedure. A 42-year-old man with multiple previous eye surgeries presented with a nonfunctioning pars plana glaucoma tube. There was no view to the tube tip, but it was presumed to be clogged with fibrin. Intravitreal tissue plasminogen activator (tPA) was injected through the pars plana which resulted in intraocular pressure control without further surgery. This new application of intravitreal tPA has not been reported previously. Future research should investigate the optimal effective and safe dose of intravitreal tPA injection to relieve such occlusions.
View details for PubMedID 19668550
Inhibition of polymorphonuclear leukocyte-mediated graft damage synergizes with short-term costimulatory blockade to prevent cardiac allograft rejection
2005; 112 (3): 320-331
The early inflammatory response during reperfusion of cardiac allografts is initiated by the infiltration of polymorphonuclear leukocytes (PMNs) into the graft. The impact of early PMN infiltration on allograft rejection compared with long-term graft survival remains poorly understood.We tested the role of CXCR2, the receptor for 2 PMN attractant chemokines, KC/CXCL1 and MIP-2/CXCL2, on intragraft inflammation and vascularized cardiac allograft rejection in a murine model. Compared with allografts retrieved from control recipients, both PMN infiltration and intragraft proinflammatory cytokine expression were significantly attenuated in allografts from CXCR2-antisera-treated wild-type or from CXCR2(-/-) recipients. Adoptive transfer of alloantigen-primed T cells rapidly infiltrated and rejected allografts in control recipients, but T-cell infiltration was significantly decreased in recipients depleted of PMNs at transplantation. The influence of early PMN-mediated inflammation on the therapeutic efficacy of costimulatory blockade to prevent allograft rejection was tested. Short-term treatment of recipients with anti-CD154 mAb or CTLA-4 Ig induced modest prolongation of cardiac allograft survival. However, CD154 mAb or CTLA-4 Ig treatment, combined with either peritransplantation PMN depletion or antibodies specific for KC/CXCL1 plus MIP-2/CXCL2, prolonged cardiac allograft survival beyond 100 days.Results suggest that strategies attenuating PMN-mediated tissue damage during reperfusion significantly improve the efficacy of short-term costimulatory blockade to prevent T-cell-mediated rejection of cardiac allografts.
View details for DOI 10.1161/CIRCULATIONAHA.104.516708
View details for Web of Science ID 000230597600006
View details for PubMedID 15998678
Alloreactive T cell responses and acute rejection of single class II MHC-disparate heart allografts are under strict regulation by CD4(+)CD25(+) T cells
JOURNAL OF IMMUNOLOGY
2005; 174 (6): 3741-3748
Skin but not vascularized cardiac allografts from B6.H-2bm12 mice are acutely rejected by C57BL/6 recipients in response to the single class II MHC disparity. The underlying mechanisms preventing acute rejection of B6.H-2bm12 heart allografts by C57BL/6 recipients were investigated. B6.H-2bm12 heart allografts induced low levels of alloreactive effector T cell priming in C57BL/6 recipients, and this priming was accompanied by low-level cellular infiltration into the allograft that quickly resolved. Recipients with long-term-surviving heart allografts were unable to reject B6.H-2bm12 skin allografts, suggesting potential down-regulatory mechanisms induced by the cardiac allografts. Depletion of CD25+ cells from C57BL/6 recipients resulted in 15-fold increases in alloreactive T cell priming and in acute rejection of B6.H-2bm12 heart grafts. Similarly, reconstitution of B6.Rag(-/-) recipients with wild-type C57BL/6 splenocytes resulted in acute rejection of B6.H-2bm12 heart grafts only if CD25+ cells were depleted. These results indicate that acute rejection of single class II MHC-disparate B6.H-2bm12 heart allografts by C57BL/6 recipients is inhibited by the emergence of CD25+ regulatory cells that restrict the clonal expansion of alloreactive T cells.
View details for Web of Science ID 000227510900076
View details for PubMedID 15749914
Early T cell response to allografts occuring prior to alloantigen priming up-regulates innate-mediated inflammation and graft necrosis
AMERICAN JOURNAL OF PATHOLOGY
2004; 165 (1): 147-157
The early inflammatory response within organ allografts is initiated by ischemia/reperfusion (I/R) and promotes subsequent alloantigen-primed T cell recruitment into and rejection of the graft. Polymorphonuclear leukocyte (PMN)-mediated tissue damage is a primary component of the early inflammation in allograft rejection. We sought to compare and elucidate the mechanism of early PMN infiltration into cardiac isografts and allografts. Despite identical production of PMN attractant chemokines, PMN infiltration following reperfusion into syngeneic and allogeneic grafts was not equivalent. PMN infiltration into isografts peaked at 9 to 12 hours post-transplant and quickly resolved. In contrast, PMN infiltration into allografts continued to elevated levels, peaking at 24 hours post-reperfusion. This amplified PMN infiltration into allografts did not resolve until 72 hours post-reperfusion and was accompanied by marked parenchymal necrosis. This early innate inflammatory response was regulated by IFN-gamma-producing CD8+ T cells present in the recipient before detectable alloantigen T cell priming. Co-culture with CD62L(low) CD8+ T cells, but not CD62L(high) CD8+ or CD62L(low) CD4+ T cells, harvested from naïve animals induced allogeneic endothelial cells to express IFN-gamma-dependent chemokines. These data demonstrate CD8+ T cell-mediated attack on the vascular endothelium of allografts within hours following organ reperfusion that amplifies innate immune-mediated intra-graft inflammation and necrosis.
View details for Web of Science ID 000222216000014
View details for PubMedID 15215170
Neutrophils mediate parenchymal tissue necrosis and accelerate the rejection of complete major histocompatibility complex-disparate cardiac allografts in the absence of interferon-gamma
AMERICAN JOURNAL OF PATHOLOGY
2003; 162 (2): 509-519
A major feature of acute rejection of cardiac allografts is an intense mononuclear cell infiltration accompanied by interferon (IFN)-gamma production. In the current study we tested the role of IFN-gamma in acute rejection of allografts by comparing the histopathology of rejection in wild-type versus IFN-gamma-/- recipients of major histocompatibility complex-mismatched cardiac grafts. Wild-type recipients rejected the allografts at days 8 to 9 after transplant but rejection was accelerated 2 to 3 days in IFN-gamma-deficient recipients. During rejection in wild-type recipients, the allografts were heavily infiltrated with CD8+ T cells and other mononuclear cells. In contrast, allografts in IFN-gamma-deficient recipients had few T cells but an intense neutrophil infiltration accompanied by extensive graft parenchymal necrosis. No difference in expression levels of neutrophil chemoattractants including Groalpha/KC, MIP-2, GCP-2, and MIP-1alpha, was observed in allografts retrieved from wild-type and IFN-gamma-/- recipients. Depletion of neutrophils from IFN-gamma-deficient recipients delayed rejection until days 8 to 10 after transplant and restored the histopathology of acute allograft rejection to that observed in allografts rejected by wild-type recipients. These results indicate the potent regulatory properties of IFN-gamma during acute rejection directed at neutrophil infiltration into allografts and mediating graft tissue necrosis.
View details for Web of Science ID 000180577100016
View details for PubMedID 12547709
Chemokines: directing leukocyte infiltration into allografts
CURRENT OPINION IN IMMUNOLOGY
2002; 14 (5): 562-568
Chemokines have been shown to play a critical role in the recruitment of leukocytes to transplanted organs. Animal models and clinical studies have demonstrated predictable temporal and spatial correlations between chemokine production and leukocyte infiltration into allografts. Antagonism of chemokines or chemokine receptors has been shown to delay leukocyte infiltration and prolong graft function, demonstrating an important role for chemokines in allograft rejection.
View details for Web of Science ID 000177716100004
View details for PubMedID 12183154
Percutaneous endocardial transfer and expression of genes to the myocardium utilizing fluoroscopic guidance
CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS
2001; 52 (2): 260-266
Experimental studies indicate that administration of angiogenic proteins or genes by the epicardial or intracoronary route can stimulate development of new collateral vessels and improve myocardial perfusion. An endocardial catheter-based approach to this therapy would obviate the need for surgery, while preserving the effectiveness of direct intramyocardial administration. Fluoroscopic guidance and prototype, preformed, coaxial catheters were used to examine the feasibility of percutaneous catheter-based adenovirus (Ad)-mediated gene transfer and expression in normal swine myocardium. The feasibility of intramyocardial administration (100 microl/injection) of a radiocontrast agent and black tissue dye to all regions of the left ventricle (septum, anterior, lateral, and inferior wall) was confirmed fluoroscopically and on postmortem examination. Injections of replication-deficient adenovirus (10 injections of 10(11) particle units/100 microl each) coding for beta-galactosidase (Adbetagal) or vascular endothelial growth factor (Ad(GV)VEGF121.10) were administered to the left ventricular free wall to examine endocardial based gene transfer and expression. beta-Galactosidase activity was detected by histochemical staining and quantitative assay in targeted regions of the myocardium. Regional VEGF expression was found to be significantly greater in targeted regions (1.3 +/- 0.4 ng/mg protein) as compared with non-targeted regions (0.3 +/- 0.1 ng/mg protein) or regions injected with control (Adbetagal) virus (0.2 +/- 0.03 ng/mg protein, P < 0.001). Catheter-based Ad mediated endocardial gene transfer and expression is feasible using percutaneous, fluoroscopically guided, preformed, coaxial catheters. This approach should be clinically useful to administer angiogenic genes to the ischemic myocardium.
View details for Web of Science ID 000166723500026
View details for PubMedID 11170342
Use of quantitative TaqMan real-time PCR to track the time-dependent distribution of gene transfer vectors in vivo
2000; 2 (6): 649-656
To assess the biodistribution and pharmacokinetics of gene transfer vectors, real-time PCR with fluorescent TaqMan chemistry was used to quantify tissue levels of adenovirus gene transfer vectors (Ad) following myocardial administration. After optimizing the detection of the genome of Ad vectors expressing human vascular endothelial growth factor (Ad(GV)VEGF121.10) and Escherichia coli cytosine deaminase (Ad(GV)CD.10), a comparison was made of intramyocardial injection versus intracoronary delivery to the left ventricle of the pig. One hour post-intramyocardial administration, the left ventricular Ad genome level was 6.2 copies per cellular genome, 26-fold higher than the level of 0.24 copies per cellular genome following intracoronary administration. Relative to the vector levels after 1 h, the amount dropped 14- and 5.5-fold by 24 h following intramyocardial and intracoronary administration, respectively. Interestingly, the vector that escaped the left ventricle after intracoronary or intramyocardial administration to pigs was found primarily within the lung, an observation in marked variance to the biodistribution of Ad vector in rodents. In this regard, after intravenous injection to the pig, 90% of the recovered vector was found in the lung, and even after intrahepatic portal vein injection, 55% of the recovered vector was in the lung. These data have important implications regarding the use of experimental animals for safety studies on administration of Ad to humans.
View details for Web of Science ID 000166225100017
View details for PubMedID 11124067
Focal angiogen therapy using intramyocardial delivery of an adenovirus vector coding for vascular endothelial growth factor 121
35th Annual Meeting of the Society-of-Thoracic-Surgeons
ELSEVIER SCIENCE INC. 2000: 14–23
Adenovirus (Ad) vector-mediated gene therapy strategies have emerged as promising modalities for the "biological revascularization" of tissues. We hypothesized that direct intramyocardial, as opposed to intracoronary, administration of an Ad vector coding for the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) would provide highly focal Ad genome levels, and increases in VEGF, ideal for inducing localized therapeutic angiogenesis.Persistence and regional distribution of the vector were assessed by TaqMan real-time quantitative polymerase chain reaction technology and enzyme-linked immunosorbent assay, after intramyocardial Ad(GV)VEGF121.10 in the rat, and either intramyocardial or intracoronary (circumflex territory) vector in Yorkshire swine. Based on these results, we assessed the focal nature of the improved cardiac blood flow in a previously reported porcine myocardial ischemia model.Intramyocardial delivery of Ad(GV)VEGF121.10 in the rat resulted in local persistence of the Ad genome that decreased 1,000-fold over 3 weeks, with peak myocardial VEGF expression 24 to 72 h after vector delivery. After intramyocardial Ad(GV)VEGF121.10 in the circumflex distribution of pigs, Ad vector genome and VEGF protein levels were more than 1,000-fold and more than 90-fold higher, respectively, in this distribution than in other myocardial regions. In comparison, intracoronary injection yielded maximum myocardial Ad genome and VEGF levels 33-fold and 9-fold lower, respectively, than that after intramyocardial delivery. Angiograms obtained 28 days after intramyocardial Ad(GV)VEGF121.10 demonstrated rapid circumflex reconstitution via collaterals localized to the region of vector administration.These studies demonstrate that direct intramyocardial administration of Ad(GV)VEGF121.10 results in focal genome and VEGF levels, including focal angiogenesis, sufficient to normalize blood flow to the ischemic myocardium, findings that are relevant to designing human trials of gene therapy-mediated cardiac angiogenesis.
View details for Web of Science ID 000084903600005
View details for PubMedID 10654479
Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs
JOURNAL OF VIROLOGY
1999; 73 (8): 6729-6742
Administration of adenovirus (Ad) vectors to immunologically naive experimental animals almost invariably results in the induction of systemic anti-Ad neutralizing antibodies. To determine if the human systemic humoral host responses to Ad vectors follow a similar pattern, we evaluated the systemic (serum) anti-Ad serotype 5 (Ad5) neutralizing antibodies in humans after administration of first generation (E1(-) E3(-)) Ad5-based gene transfer vectors to different hosts. AdGVCFTR.10 (carrying the normal human cystic fibrosis [CF] transmembrane regulator cDNA) was sprayed (8 x 10(7) to 2 x 10(10) particle units [PU]) repetitively (every 3 months or every 2 weeks) to the airway epithelium of 15 individuals with CF. AdGVCD.10 (carrying the Escherichia coli cytosine deaminase gene) was administered (8 x 10(8) to 8 x 10(9) PU; once a week, twice) directly to liver metastasis of five individuals with colon cancer and by the intradermal route (8 x 10(7) to 8 x 10(9) PU, single administration) to six healthy individuals. AdGVVEGF121.10 (carrying the human vascular endothelial growth factor 121 cDNA) was administered (4 x 10(8) to 4 x 10(9.5) PU, single administration) directly to the myocardium of 11 individuals with ischemic heart disease. Ad vector administration to the airways of individuals with CF evoked no or minimal serum neutralizing antibodies, even with repetitive administration. In contrast, intratumor administration of an Ad vector to individuals with metastatic colon cancer resulted in a robust antibody response, with anti-Ad neutralizing antibody titers of 10(2) to >10(4). Healthy individuals responded to single intradermal Ad vector variably, from induction of no neutralizing anti-Ad antibodies to titers of 5 x 10(3). Likewise, individuals with ischemic heart disease had a variable response to single intramyocardial vector administration, ranging from minimal neutralizing antibody levels to titers of 10(4). Evaluation of the data from all trials showed no correlation between the peak serum neutralizing anti-Ad response and the dose of Ad vector administered (P > 0.1, all comparisons). In contrast, there was a striking correlation between the peak anti-Ad5 neutralizing antibody levels evoked by vector administration and the level of preexisting anti-Ad5 antibodies (P = 0.0001). Thus, unlike the case for experimental animals, administration of Ad vectors to humans does not invariably evoke a systemic anti-Ad neutralizing antibody response. In humans, the extent of the response is dictated by preexisting antibody titers and modified by route of administration but is not dose dependent. Since the extent of anti-Ad neutralizing antibodies will likely modify the efficacy of administration of Ad vectors, these observations are of fundamental importance in designing human gene therapy trials and in interpreting the efficacy of Ad vector-mediated gene transfer.
View details for Web of Science ID 000081377400062
View details for PubMedID 10400771
Exogenous control of cardiac gene therapy: Evidence of regulated myocardial transgene expression after adenovirus and adeno-associated virus transfer of expression cassettes containing corticosteroid response element promoters
JOURNAL OF THORACIC AND CARDIOVASCULAR SURGERY
1999; 118 (1): 26-34
Because of the relative inaccessibility of the heart for repeated gene therapy, it would be useful to regulate the expression of transgenes delivered in a single dose of a gene therapy vector. Incorporation into the vector of a regulatable promoter that is responsive to pharmacologic agents that are widely used and well tolerated in clinical practice represents such a control strategy.A replication-deficient adenovirus or an adeno-associated virus containing a chimeric promoter composed of 5 glucocorticoid response elements and the murine thrombopoietin complementary DNA (AdGRE.mTPO or AAVGRE.mTPO) was administered to the hearts of Sprague-Dawley rats. Platelet levels were evaluated as a reporter of transgene activity with or without dexamethasone. For comparison, rats received a control adenovirus vector, AdCMV.mTPO or AdCMV.Null, and the control adeno-associated virus vector AAVCMV.luc, which encodes for the firefly luciferase (luc) gene.Platelet elevation in the AdGRE.mTPO group peaked 4 days after dexamethasone administration, with a return to baseline 1 week after the initial corticosteroid dose. Subsequent dexamethasone administration at 2 and 4 weeks resulted in similar but progressively decreased responses. The AAVGRE.mTPO group had 5 peak platelet levels to a minimum of 2.2-fold with respect to baseline without diminution with subsequent dexamethasone administrations out to 169 days. In contrast, the AdCMV.Null and AAVCMV.luc groups demonstrated no increase in platelet counts and the AdCMV.mTPO group demonstrated a slow rise to a single peak platelet count independent of dexamethasone administration.It may be possible to control on demand the expression of a gene transferred to the heart. This strategy should be useful in cardiac gene therapy.
View details for Web of Science ID 000081321800007
View details for PubMedID 10384181
Safety of direct myocardial administration of an adenovirus vector encoding vascular endothelial growth factor 121
HUMAN GENE THERAPY
1999; 10 (8): 1331-1348
A gene therapy strategy involving direct myocardial administration of an adenovirus (Ad) vector encoding the vascular endothelial growth factor 121 cDNA (Ad(GV)VEGF121.10) has been shown to be capable of "biological revascularization" of ischemic myocardium in an established porcine model [Mack, C.A. (1998). J. Thorac. Cardiovasc. Surg. 115, 168-177]. The present study evaluates the local and systemic safety of this therapy in this porcine ischemia model and in normal mice. Myocardial ischemia was induced in Yorkshire swine with an ameroid constrictor 21 days prior to vector administration. Ad(GV)VEGF121.10 (10(9) or 10(10) PFU), Ad5 wild type (10(9) PFU), AdNull (control vector with no transgene; 10(9) PFU), saline, or no injection (naive) was administered in 10 sites in the ischemic, circumflex distribution of the myocardium. Toxicity was assessed by survival, serial echocardiography, blood analyses, and myocardial and liver histology at 3 and 28 days after vector administration. All pigs survived to sacrifice, except for one animal in the Ad(GV)VEGF121.10 (10(10) PFU) group, which died as a result of oversedation. Echocardiograms of Ad(GV)VEGF121.10-treated pigs demonstrated no differences in pericardial effusion, mitral valve regurgitation, or regional wall motion compared with control pigs. Intramyocardial administration of Ad(GV)VEGF121.10 included only minimal myocardial inflammation and necrosis, and no hepatic inflammation or necrosis. Only a mild elevation of the white blood cell count was encountered on day 3, which was transient and self-limited in the Ad(GV)VEGF121.10 group as compared with the saline-treated animals. As a measure of inadvertent intravascular administration of vector, normal C57/BL6 mice received intravenous Ad(GV)VEGF121.10 (10(4), 10(6), 5 x 10(7), or 10(9) PFU), AdNull (5 x 10(7) or 10(9) PFU), or saline. Toxicity was assessed by survival, blood analyses, and organ histology at 3 and 7 days after vector administration. A separate group of C57/BL6 mice received intravenous AdmVEGF164 (Ad vector encoding the murine VEGF164 cDNA), Ad(GV)VEGF121.10, AdNull (10(8) PFU each group), or saline to assess duration of expression and safety of a homologous transgene. All mice survived to sacrifice except for 40% of the mice in the highest (10(9) PFU; a dose more than 10(3)-fold higher by body weight than the efficacious dose in pigs) Ad(GV)VEGF121.10 dose group, which died on days 5-6 after vector administration. The only differences seen in the blood analyses between treated and control mice were in the very high Ad(GV)VEGF121.10 dose group (10(9) PFU), which demonstrated an anemia as well as an increase in alkaline phosphatase when compared with all other treatment groups. Hepatic VEGF levels by ELISA in AdmVEGF164-treated mice did not persist beyond 14 days after vector administration, suggesting that persistent expression of a homologous VEGF gene transferred with an Ad vector is not a significant safety risk. Although this is not a chronic toxicity study, these data demonstrate the safety of direct myocardial administration of Ad(GV)VEGF121.10, and support the potential use of this strategy to treat human myocardial ischemia.
View details for Web of Science ID 000080493500008
View details for PubMedID 10365664